The brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. In vertebrates, the brain is located in the head, protected by the skull and close to the primary sensory apparatus of vision, hearing, balance, taste, and smell. Brains can be extremely complex. The human brain contains roughly 100 billion neurons, linked with up to 10,000 synaptic connections each. Each cubic millimeter of cerebral cortex contains roughly one billion synapses, which at an average of 1,000 synaptic connections is 1,000,000 neurons per cubic millimeter, equivalent to 100 neurons per millimeter or a neuron every 10 μm. These neurons communicate with one another by means of long protoplasmic fibers called axons and dendrites, which carry trains of signal pulses, called action potentials, to distant parts of the brain or body and target them to specific recipient cells.
Neurological ailments typically afflict patients as they age but they can present themselves at any time in an individual's lifetime. Among these ailments are Alzheimer's disease, Asperger's syndrome, cerebral palsy, Creutzfeldt-Jakob disease, Epilepsy, Fibromyalgia, Motor Neurone Disease, Parkinson's disease, Schizophrenia, Spasticity, Tourette syndrome, etc as well as more common events such as headaches, backaches, migraines, repetitive stress injuries etc. Such ailments present medical scientists with one of their greatest challenges. While research continually increases knowledge of aging and related diseases, many of the details of how the brain works (and doesn't work) remain a mystery.
Additionally paralysis, loss, or impairment of motor function due to personal accident or disease of the human nervous system reduces the ability of the affected individual to move or respond despite the capacity to think, form intentions, and make decisions. In spinal cord injuries, strokes, and diseases such as amyotrophic lateral sclerosis, the neurons that convey commands from a specific part of the brain to a desired muscle can be injured. Despite the significant strides made by basic and clinical research, few therapeutic options are available at present for restoring voluntary motor control of the limbs in patients suffering from extensive traumatic or degenerative lesions of the motor system. The prevalence of severe body paralysis is high, particularly among young adults. For instance, among the leading causes of permanent paralysis, traumatic spinal cord injuries, produced by traffic accidents, acts of violence, or falls account for nearly 11,000 new cases each year in the United States alone, see A. I. Nobunaga et al “Recent Demographic and Injury Trends in People Served by the Model Spinal Cord Injury Care Systems” (Arch. Phys. Med. Rehabil. Vol. 80 Nov. 1999, pp 1372-1382) and M. A. L. Nicolelis “Brain-Machine Interfaces to Restore Motor Function and Probe Neural Circuits” (Nature Reviews Vol. 4, May 1993, pp 417-422). The National Spinal Cord Injury Association estimates there are 450,000 people living within spinal cord injury in the United States of America alone; others put the estimate more conservatively at 250,000 costing the United States of America an estimated $9.7 billion per annum (Centers for Diseases Control and Prevention (CDC)).
About half of these patients are quadriplegic, which means that, owing to injury to the cervical spinal cord, they cannot move any of their limbs or any other muscle below the neck. Quadriplegics depend on continuous assistance to accomplish even the simplest of motor acts. Whereas most of us take for granted our ability to breathe, eat and drink, a quadriplegic patient usually cannot do any of these without the assistance of a machine (such as a ventilator) or a caretaker. For this reason, restoring even the smallest of motor skills in these patients can have a profound effect on their quality of life. Recent experimental demonstrations in rodents, primates, and patients have raised interest in the proposition that neural prosthetic devices designed to bypass spinal cord lesions could be used to restore basic motor functions in patients suffering from severe body paralysis.
Brain machine interfaces or neural prosthetics represent an engineering approach to bypass paralytic parts of human body. Implanted arrays of neural recording electrodes and electronics acquisition devices are employed to monitor in real-time the brain electrical activities or neural electropotentials that reflect the intentions of a paralyzed human. These signals are the inputs for the prosthesis or computer system they are trying to use. Software algorithms analyze these signals to form the link between recorded neural signals and the thoughts of the paralyzed patient that are decoded to drive the external robotic prosthetic devices.
In research studies the electrical stimulation of deep brain structures (deep brain stimulation, or “DBS”) has been established and may be developed into an effective treatment modality for advanced Parkinson's disease and essential tremors arising therefrom. DBS is also being evaluated as a treatment for other neurological conditions and appears to be useful in the treatment of several types of dystonias and hyperkinetic disorders. While the range of clinical applications for DBS has expanded in recent years, its mechanism of action is not completely understood. In fact studies directed towards an elucidation of the physiologic underpinnings of DBS certainly have been aided by microelectrode arrays for chronic implantation into animals, including subhuman primates, and which deliver highly localized electrical stimulation into the target nucleus, and which include the capability of monitoring the response to the electrical stimulation by individual neurons in the target nucleus. It is important that such microelectrodes be able to deliver stimulation for an extended interval, and without injury to the tissue. An array of independently controllable stimulating microelectrodes distributed throughout the target nucleus would permit precise control of the spatial distribution of the stimulation, by stimulating either with single microelectrodes or with a subgroup of microelectrodes that could be pulsed either simultaneously or sequentially.
Amongst prior art microelectrodes are those based upon printed circuit board (PCB) approaches such as M. A. L. Nicolesi et al in U.S. Pat. No. 6,993,392 entitled “Miniaturized High Density Multi-Channel Electrode Array for Long-Term Neuronal Recordings” and J. C. Williams et al in U.S. Pat. No. 7,504,069 entitled “Micro Device for High Resolution Delivery and Monitoring of Stimuli to a Biological Object In-Vitro”. Others reported microfilament two-dimensional arrays of flexible materials such as plastics with conductive coatings such as S. C. Jacobsen et al in US Patent Application 2007/0,167,815 entitled “Multi-Element Probe Array”, whilst others have exploited machinable ceramics to form thin probes such as K. A. Moxon et al in U.S. Pat. No. 6,834,200 entitled “Ceramic Based Multi-Site Electrode Arrays and Methods for Their Production”.
Silicon has also formed the basis of developments for neuronal probes due to its excellent micromachining properties, compatibility with high volume semiconductor processing techniques and the ability to integrate CMOS electronics for signal conditioning, detected signal amplification etc. Such developments including for example D. B. McCreery in US patent application entitled “Multi-Electrode Array for Chronic Deep Brain Micro-Stimulation for Recording”, P. K. Campbell et al in “Silicon based 3D Neural Interface, Manufacturing Processes for a Intracortical Electrode Array” (IEEE Trans. Biomed. Eng. Vol. 38 No. 3 pp 758-768 August 1991), and D. J. Anderson in “Current and Future Uses of High Density Implant Arrays for Functional Electrical Stimulation Systems: (International Functional Electrical Stimulation Systems 2003, Keynote Address, Proc. Vol. 2 (1), September 2003).
The accurate understanding of brain functions, and potentially accurate interpretation of neurological activity in specific localized brain regions such as motor control, speech etc, requires that we have knowledge of the interaction of separate brain regions and their functional connectivity during particular cognitive or motor tasks. This requires more than simply detecting neuron activity within specific regions of the brain. There are many sources of information in addition to the electrical activities of neural communications which can be in the form of spikes or local field potentials. Included amongst these other sources of signals are neural biomarkers such as oxygen (O2), acidity (pH), potassium (K+) ions, and sodium (Na+) ions. These signals can aid to classical techniques in decoding the distributed patterns of brain activity associated with specific motor activity. There is much evidence from functional magnetic resonance imaging (FMRI), which provides functional connectivity maps of distinct spatial distributions of temporally correlated brain regions, that tissue oxygenation is related to neural electrical activities, see for example J. K. Thompson et al in “Single-Neuron Activity and Tissue Oxygenation in the Cerebral Cortex” (Science, Vol. 299, No. 5609, February 2003, pp 1070-1072; (http://tsolab.org/jclub/20031006/freeman.pdf) and A. Devor et al in “Coupling of Total Haemoglobin Concentration, Oxygenation, and Neural Activity in Rat Somatosensory Cortex” (Neuron, Vol. 39, pp. 353-359, Jul. 17, 2003; http://www.nmr.mgh.harvard.edu/PMI/PDF/2003/Devor_Neuron—39—353—2003.pdf).
FMRI infers neural activity by measuring small changes in the de-oxygenation of hemoglobin in a cortical area. In contrast to oxygenated hemoglobin, deoxygenated hemoglobin disrupts a magnetic field which leads to an enhancement of the MRI. Faster optical imaging techniques have to be used however to assess the temporal properties of the oxygen response which represents a continuous stream of information alongside the electrical activity. Several researchers have reported that O2 concentration ascribed to immediate O2 consumption can be observed 100 milliseconds after activity onset, see for example A. Grinvald et al in “Non-Invasive Visualization of Cortical Columns by fMRI,” (Nature Neuroscience, vol. 3, pp. 105-107, February 2000). Thus, hemodynamic events are tightly coupled to cortical electrical activity immediately following activation. O2 pressure changes have also been shown to be highly specific for local increases in neuronal activity and correlated with the degree of activity.
Thus, to establish a quantitative understanding of this relationship at a sub-millimeter scale, it would be beneficial to provide an integrated probe platform to hold oxygen and/or other biomarkers' sensors along with recording sites to measure the neural electrical activity. The biomarker sensors within the integrated probe platform exploiting optical techniques alongside the electrical circuitry for the neural measurements. Such an integrated probe platform would be important for the accurate control of neural prosthetics and brain machine interfaces as well as helping in providing answers to complex brain diseases and disorders. Such a hybrid microprobe that has the capability to simultaneously record both the neural electrical activities along with chemical activity, such as O2, pH, K+, and Na+ for example, using an optical sensor will result in a significant increase of the information yield and enhance deciphering the nature of the information flow and function when compared to standard probes that can only record electrical activities
It would also be beneficial in some instances for the sensor elements to include physical biological filters such that only the specific target molecules or groups of molecules were able to interact with the sensor element. As such it would be beneficial for the integrated probe platform to include physical membrane filter elements as well as the optical interrogation elements, electronics, etc.
It would also be beneficial if the integrated probe platform was formed as a hybrid silicon circuit allowing the platform to leverage the cost benefits of high volume, large wafer silicon processing and provide opportunity for the potential integration of electrical and optical circuit elements allowing fully monolithic optically interrogated integrated sensor devices and arrays. Further for maximum flexibility hybrid integration of optical emitter and detector devices would allow a wider range of sensor materials to be employed.